N-methyl glycine derivative of trichlorophenol



United States Patent Ofi ice 3,236,884 Patented Feb. 22, 1966 7 This application is a continuation-in-part of applicants copending application Serial No. 595,609, filed July 3, 1956, and now abandoned.

The present invention relates to novel compositions of matter and more particularly to N-methyl glycine derivatives of phenols and phenol derivatives.

The antiseptic properties of phenols and phenol derivatives including thymol, cresol, naphthol and other substituted phenols are well known. Halogenation greatly increases the antiseptic action of these compounds so that in some instances, such as in the case of pentachlorophenol, the antiseptic action is increased as much as 50 times over that of simple phenols.

While phenols and phenol derivatives such as thymols, cresols and naphthols have a strong antiseptic action, however, they are so highly toxic that their use is quite limited.

It has been found that when N-methyl glycine (commonly known as sarcosine) derivatives of these compounds are formed by the Mannich reaction, the toxicity is greatly reduced and the resulting derivatives are potent and useful antibiotic agents. Because of their low toxicity and high antibiotic potency, they may be used in relatively crude form for applications such as the sterilization of clothing, houses, and the like.

In addition to the feature of the present invention relating to the reduction in toxicity of phenols, another important aspect of the present invention relates to the formulation of a class of antiseptic-antibiotics through the substitution on the phenolic benzoid nucleus of a Manniched N-methyl glycine radical. More specifically, this aspect of the invention makes possible the use of antiseptic compounds as antibiotics through the Manniching of one or more N-methyl glycine sub-stituents on the phenolic benzoid nucleus, whereby the antiseptic is imparted the additional quality of being a food substance for living organisms. Any substituted or halogenated phenol or phenol derivative and dihydric and trihydric phenols may be used in forming N-methyl glycine derivatives of the present invention so long as either the ortho or para poistions or both are open.

Generally speaking, the present invention is directed to compounds of the formula wherein m is 1-2;

is a phenolic nucleus; R is selected from the group consisting of hydrogen, methyl, ethyl, ammonium and nontoxic basic metal atoms; and the I" $11: CH2NCH2COOR1 substituent is positioned either ortho or para to the phenolic hydroxyl radical when m=1 and in both of these positions when-m=2.

The present invention is also directed to the following specific compounds:

oml icmooon] wherein m is 1-2; n is l-4; R is selected from the group consisting of hydrogen, methyl, ethyl, ammonium and non-toxic basic metal atoms; and the substituent is positioned either ortho or para to the OH radical when m-=1 and in both of these positions when m-2;

cmfiggcmi romoooa] wherein m and R have the significance set forth in Forinula l and the substituent is positioned as set forth in Formula 1; and

OH 51H: (CHahOH CHzNCHiCOOR solution of sodium sarcosinate (0.025 mole) were added. The reaction mixture was cooled in an ice bath and 3.1

g. (0.02 mole) of 37% aqueous formaldehyde were tdded. --The solution was allowed. to stand for. one hour.

HCHO Cl CHgN-CHzCOONa At this stage, the liquid contains excess N-methyl glyzine and formaldehyde but these impurities can be tolerlted for many uses, such as sterilizing clothing. When he compound is to be used in, this form, it is usually referable tofiuse the bare minimum of formaldehyde iecessary for the reaction and to use only a small (about 50% mol.) excess of N-methyl glycine.

To purify the compound further, concentrated HCl vas added to about pH 3 and the reaction mixture conxentrated to about 15 ml. and chilled. This step is shown )y the following equation:

OH CH3 )1 CHZI TCHZCOONa H01 OH CH:

Cl CHQI ICHZCOOH NaCl The mother liquor was decanted or filtered from the recipitate which formed and the precipitate may be reated with 15 ml.of 95% ethanol to induce crystallizaion. This solid was then recrystallized from 95 ethanol give 1.0 g. (3%) tan crystals, M.P. 184 dec. (when )laced on a melting point block at 175 Additional aroduct may be obtained by further concentrating the mother liquor.

A large scale run with 0.12 mole of the trichlorophenol, lsing solid trioxymethylene instead of aqueous HCHO, gave a similar'product in about 40% yield. An equivtlent Weight determination was made as follows: found, .98; calcd., 299.

The purified compound may be made soluble by addng a salt such as sodium bicarbonate and the resulting roduct has very low toxicity, the LD on rats being tbout 200 mg. per kg.

The antibacterial efl ect of the soluble purified product vas tested in the following manner: Disks were impreglated with the product and impregnated disks were placed an the surface of blood agar plates which had previously een seeded with the appropriate organism. Each disk :ontained about 0.175 mg. of the product and the plates vere incubated at 37 C. for twenty hours. The zone f inhibition, that is, the zone about the impregnated disk [1 which no growth was seen after incubation, reflected he antibacterial effect. The following table shows the esults of these tests:

When other halogenated or substituted phenols are .used, the reaction proceeds in substantially the same way.

In some instances, the hydrochloric acid reacts with excess N-methyl glycine to form soluble salts which are difficult to separate, but for many applications, this is unimportant.

EXAMPLE 2 The N-methyl glycine Mwrmich derivative of 6-chl0r0' thymol 6-chloro thymol, 3.7 g. (.02 mole) was dissolved in 10 cc. of absolute alcohol and added to 43 g. of an'a'queous N-methyl glycine solution containing about 13% of the sodium salt of N-methyl glycine. This was chilled and 1.2 g. (.04 mole) of paraformaldehyde was added. The mixture was then allowed to stand at room temperature for about 30 minutes. It was then refluxed for four hours using a glascol electric heater; the mixture became homogeneous soon after refluxing started. At the end of the reaction period, the contents of the flask were allowed to cool and diluted HCl was added slowly until the pH of the solution reached about 2.0, or until no further white solid appeared to separate. It was then washed with cold water and filtered, giving 4.7 of crude product, which softened at 70 and melted (with flowing) at about Recrystallization from benzene gave a product melting at -157".

The reactions are indicated by the'following equations:

OH; on

CH3 CH i nono g HNCH'zCOQNa on; OH 111:

o11 CHzNCHzCOONa CH3 on CHzN-CHzGOONa H01 CH3 on; OH on.

/OH omrwomooon CH2:

CH3 NaCl The other N-methyl glycine derivatives embraced by the present invention may be. formed in the same manner.

In each of the examples set forth above, the method of preparing the mono-Manniched compound was set forth. If desired, the di-Manniched derivative may be prepared (where both the ortho and para positions on the phenolic nucleus are open) where a suflicient excess of Mannichreagent is used.

The resulting products have strong antibiotic and antiseptic effects without allergic side effects. The purified products can be used in various ways, i'.e;, orally and by injection as antibiotics and in purified or crude form as additives to detergents, 'in soapsjand inresins or gums for impregnation. 1 t

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are there-fore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claim rather than'by the foregoing description,

and all the changes which come within the meaning and range of equivalency of the claim are therefore intended to be embraced therein.

5 6 What is claimed and desired to be secured by United References Cited by the Examiner States Letters Patent iSi UNITED STATES PATENTS h A 0ft 6 i 2,717,263 9/1955 McKinney et a1. 260471 3 cmr romooon 5 LORRAINE A. WEINBERGER, Primary Examiner.

(01) CHARLES B. PARKER, LEON ZITVER, Examiners. 

